1som



Acetylcholinesterase inhibited by nerve agent soman

(see also AChE inhibitors and substrates, 2wfz, 2wg0, 2wg1, and 1cfj)

Biological Function
Acetylcholinesterase (AChE) is a key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, acetylcholine (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) nerve agents is attributed primarily to their being potent AChE inhibitors.

Overview
Organophosphorus (OP)acid anhydride nerve agents are potent inhibitors which rapidly phosphonylate AChE and then may undergo an internal dealkylation reaction (called "aging") to produce an OP-enzyme conjugate that cannot be reactivated.





To understand the basis for irreversible inhibition, we solved the structure of the aged conjugate obtained by reaction of Torpedo californica AChE (TcAChE) with O-pinacolylmethylphosphonofluoridate (soman) by X-ray crystallography to 2.2Å resolution. The highest positive difference density peak corresponded to the OP phosphorus and was located within covalent bonding distance of the active-site serine (S200). The OP-oxygen atoms are within hydrogen-bonding distance of four potential donors from catalytic subsites of the enzyme, suggesting that electrostatic forces significantly stabilize the aged enzyme. The methyl group of soman occupies the acyl binding pocket, bounded by Trp233, Phe288, and Phe290. The active sites of aged sarin-TcAChE (1cfj) and soman-TcAChE were essentially identical and provided structural models for the negatively charged, tetrahedral intermediate that occurs during deacylation with the natural substrate, acetylcholine.

About this Structure
1SOM is a Single protein structure of sequence from Torpedo californica with NAG, UNX and VXA as ligands. Active as Acetylcholinesterase, with EC number 3.1.1.7 Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level., Millard CB, Kryger G, Ordentlich A, Greenblatt HM, Harel M, Raves ML, Segall Y, Barak D, Shafferman A, Silman I, Sussman JL, Biochemistry. 1999 Jun 1;38(22):7032-9. PMID:10353814